The long term objective of the proposed research is to develop a mechanistic basis for improving the oral delivery of peptide and peptide like drugs. The results of the previous grant period have (1) determined the intestinal transport parameters of the Beta-lactam antibiotics; (2) synthesized peptide prodrugs of alpha methyldopa and shown that they have much higher intestinal membrane permeabilities; (3) that these peptide prodrugs are hydrolyzed by mucosal cell enzymes; and (4) shown that a theoretical framework for estimating oral drug absorption is successful for both passive and carrier mediated compounds. In addition, the novel finding that ACE inhibitors (captopril and enalapril) are absorbed by the peptide carrier pathway and that captopril is a substrate for the mucosal cell prolidase enzyme greatly increases the therapeutic significance of these studies. The specific aims for the proposed grant period are: (1) Extend the experimental determination of mucosal cell transport parameters to a wider range of di- and tripeptide analogs in order to develop a basis for the molecular structural requirements for this membrane transport system. (2) Develop binding site models based on the transport parameters and use the models to guide further binding site model refinement, compound selection and prodrug testing. (3) Develop and extend a prodrug approach to improving oral drug delivery using the peptide carrier transport pathway combined with the investigation of cytosolic enzymes as the hydrolysis (reconversion) sites. (4) Extend the investigation of oral peptide absorption and metabolism to peptides in the 500 to 2000 molecular weight range. (5) Develop and extend an intestinal absorption model that will: (a) predict the extent of absorption of compounds whose absorption mechanism is carrier mediated, e.g., Beta-lactam antibiotics and ACE inhibitors: (b) account for nonlinear factors such as solubility/dissolution limits, nonlinear (concentration dependent) membrane permeability and luminal and brush-border metabolism: (c) account for drug-drug and drug-nutrient (food) interactions. The further development of the structural requirements for the peptide carrier and the extension to larger peptides, combined with the development of models that can estimate human oral delivery will provide a basis for improving the oral delivery of peptides. The results of the proposed research will increase the likelihood that the therapeutic benefits of peptide and peptide-like drugs based on peptides of high intrinsic activity, e.g., ACE inhibitors, renin inhibitors, enkephalin analogs, LH-RH analogs, atrial peptides, growth hormones, etc., can be used to improve human health.